Association between external training loads and injury incidence during 44 weeks of military training

Military training is physically arduous and associated with high injury incidence. Unlike in high-performance sport, the interaction between training load and injury has not been extensively researched in military personnel. Sixty-three (43 men, 20 women; age 24 ± 2 years; stature 1.76 ± 0.09 m; body mass 79.1 ± 10.8 kg) British Army Officer Cadets undergoing 44 weeks of training at the Royal Military Academy Sandhurst volunteered to participate. Weekly training load (cumulative 7-day moderate-vigorous physical activity [MVPA], vigorous PA [VPA] and the ratio between MVPA and sedentary-light PA [SLPA; MVPA:SLPA]) was monitored using a wrist-worn accelerometer (GENEActiv, UK). Self-report injury data were collected and combined with musculoskeletal injuries recorded at the Academy medical centre. Training loads were divided into quartiles with the lowest load group used as the reference to enable comparisons using Odds Ratios (OR) and 95% confidence intervals (95% CI). Overall injury incidence was 60% with the most common injury sites being the ankle (22%) and knee (18%). High (load; OR; 95% CI [>2327 mins; 3.44; 1.80–6.56]) weekly cumulative MVPA exposure significantly increased odds of injury. Similarly, likelihood of injury significantly increased when exposed to low-moderate (0.42–0.47; 2.45 [1.19–5.04]), high-moderate (0.48–0.51;2.48 [1.21–5.10]) and high MVPA:SLPA loads (>0.51; 3.60 [1.80–7.21]). High MVPA, and high-moderate MVPA:SLPA increased odds of injury by ~2.0–3.5 fold, suggesting that the ratio of workload to recovery is important for mitigating injury occurrence

Seladin-1 expression is regulated by promoter methylation in adrenal cancer

<p>Abstract</p> <p>Background</p> <p>Seladin-1 overexpression exerts a protective mechanism against apoptosis. Seladin-1 mRNA is variably expressed in normal human tissues. Adrenal glands show the highest levels of seladin-1 expression, which are significantly reduced in adrenal carcinomas (ACC). Since up to now seladin-1 mutations were not described, we investigated whether promoter methylation could account for the down-regulation of seladin-1 expression in ACC.</p> <p>Methods</p> <p>A methylation sensitive site was identified in the seladin-1 gene. We treated DNA extracted from two ACC cell lines (H295R and SW13) with the demethylating agent 5-Aza-2-deoxycytidine (5-Aza). Furthermore, to evaluate the presence of an epigenetic regulation also 'in vivo', seladin-1 methylation and its mRNA expression were measured in 9 ACC and in 5 normal adrenal glands.</p> <p>Results</p> <p>The treatment of cell lines with 5-Aza induced a significant increase of seladin-1 mRNA expression in H295R (fold increase, F.I. = 1.8; p = 0.02) and SW13 (F.I. = 2.9; p = 0.03). In ACC, methylation density of seladin-1 promoter was higher (2682 ± 686) than in normal adrenal glands (362 ± 97; p = 0.02). Seladin-1 mRNA expression in ACC (1452 ± 196) was significantly lower than in normal adrenal glands (3614 ± 949; p = 0.01).</p> <p>Conclusion</p> <p>On this basis, methylation could be involved in the altered pattern of seladin-1 gene expression in ACC.</p

Characterisation of a Desmosterol Reductase Involved in Phytosterol Dealkylation in the Silkworm, Bombyx mori

Most species of invertebrate animals cannot synthesise sterols de novo and many that feed on plants dealkylate phytosterols (mostly C29 and C28) yielding cholesterol (C27). The final step of this dealkylation pathway involves desmosterol reductase (DHCR24)-catalysed reduction of desmosterol to cholesterol. We now report the molecular characterisation in the silkworm, Bombyx mori, of such a desmosterol reductase involved in production of cholesterol from phytosterol, rather than in de novo synthesis of cholesterol. Phylogenomic analysis of putative desmosterol reductases revealed the occurrence of various clades that allowed for the identification of a strong reductase candidate gene in Bombyx mori (BGIBMGA 005735). Following PCR-based cloning of the cDNA (1.6 kb) and its heterologous expression in Saccharomyces cerevisae, the recombinant protein catalysed reduction of desmosterol to cholesterol in an NADH- and FAD- dependent reaction

The Toll→NFκB Signaling Pathway Mediates the Neuropathological Effects of the Human Alzheimer's Aβ42 Polypeptide in Drosophila

Alzheimer's (AD) is a progressive neurodegenerative disease that afflicts a significant fraction of older individuals. Although a proteolytic product of the Amyloid precursor protein, the Αβ42 polypeptide, has been directly implicated in the disease, the genes and biological pathways that are deployed during the process of Αβ42 induced neurodegeneration are not well understood and remain controversial. To identify genes and pathways that mediated Αβ42 induced neurodegeneration we took advantage of a Drosophila model for AD disease in which ectopically expressed human Αβ42 polypeptide induces cell death and tissue degeneration in the compound eye. One of the genes identified in our genetic screen is Toll (Tl). It encodes the receptor for the highly conserved Tl→NFkB innate immunity/inflammatory pathway and is a fly homolog of the mammalian Interleukin-1 (Ilk-1) receptor. We found that Tl loss-of-function mutations dominantly suppress the neuropathological effects of the Αβ42 polypeptide while gain-of-function mutations that increase receptor activity dominantly enhance them. Furthermore, we present evidence demonstrating that Tl and key downstream components of the innate immunity/inflammatory pathway play a central role in mediating the neuropathological activities of Αβ42. We show that the deleterious effects of Αβ42 can be suppressed by genetic manipulations of the Tl→NFkB pathway that downregulate signal transduction. Conversely, manipulations that upregulate signal transduction exacerbate the deleterious effects of Aβ42. Since postmortem studies have shown that the Ilk-1→NFkB innate immunity pathway is substantially upregulated in the brains of AD patients, the demonstration that the Tl→NFkB signaling actively promotes the process of Αβ42 induced cell death and tissue degeneration in flies points to possible therapeutic targets and strategies

A Functional Misexpression Screen Uncovers a Role for Enabled in Progressive Neurodegeneration

Drosophila is a well-established model to study the molecular basis of neurodegenerative diseases. We carried out a misexpression screen to identify genes involved in neurodegeneration examining locomotor behavior in young and aged flies. We hypothesized that a progressive loss of rhythmic activity could reveal novel genes involved in neurodegenerative mechanisms. One of the interesting candidates showing progressive arrhythmicity has reduced enabled (ena) levels. ena down-regulation gave rise to progressive vacuolization in specific regions of the adult brain. Abnormal staining of pre-synaptic markers such as cystein string protein (CSP) suggest that axonal transport could underlie the neurodegeneration observed in the mutant. Reduced ena levels correlated with increased apoptosis, which could be rescued in the presence of p35, a general Caspase inhibitor. Thus, this mutant recapitulates two important features of human neurodegenerative diseases, i.e., vulnerability of certain neuronal populations and progressive degeneration, offering a unique scenario in which to unravel the specific mechanisms in an easily tractable organism

Role of X11 and ubiquilin as In Vivo Regulators of the Amyloid Precursor Protein in Drosophila

The Amyloid Precursor Protein (APP) undergoes sequential proteolytic cleavages through the action of β- and γ-secretase, which result in the generation of toxic β-amyloid (Aβ) peptides and a C-terminal fragment consisting of the intracellular domain of APP (AICD). Mutations leading to increased APP levels or alterations in APP cleavage cause familial Alzheimer's disease (AD). Thus, identification of factors that regulate APP steady state levels and/or APP cleavage by γ-secretase is likely to provide insight into AD pathogenesis. Here, using transgenic flies that act as reporters for endogenous γ-secretase activity and/or APP levels (GAMAREP), and for the APP intracellular domain (AICDREP), we identified mutations in X11L and ubiquilin (ubqn) as genetic modifiers of APP. Human homologs of both X11L (X11/Mint) and Ubqn (UBQLN1) have been implicated in AD pathogenesis. In contrast to previous reports, we show that overexpression of X11L or human X11 does not alter γ-secretase cleavage of APP or Notch, another γ-secretase substrate. Instead, expression of either X11L or human X11 regulates APP at the level of the AICD, and this activity requires the phosphotyrosine binding (PTB) domain of X11. In contrast, Ubqn regulates the levels of APP: loss of ubqn function leads to a decrease in the steady state levels of APP, while increased ubqn expression results in an increase in APP levels. Ubqn physically binds to APP, an interaction that depends on its ubiquitin-associated (UBA) domain, suggesting that direct physical interactions may underlie Ubqn-dependent regulation of APP. Together, our studies identify X11L and Ubqn as in vivo regulators of APP. Since increased expression of X11 attenuates Aβ production and/or secretion in APP transgenic mice, but does not act on γ-secretase directly, X11 may represent an attractive therapeutic target for AD